The success of chemotherapeutic treatment of primary ovarian cancer, especially metastatic cells growing in ascitic fluid is limited by intrinsic and acquired resistance of cancer cells and adverse side effects of chemotherapy. Based on the results of our previous study and literature data, we hypothesized, that substantial enhancement in the effectiveness of treatment and imaging of drug resistant ovarian cancer and metastases can be achieved by the (1) induction of cancer cell death by at least two different anticancer drugs, (2) suppression of cancer cell resistance by siRNA targeted to proteins that play key roles in such resistance and (3) targeting drugs, imaging agents and siRNA specifically to ovarian cancer cells in primary tumor and metastases. Such an objective can only be achieved if several anticancer drugs are delivered to the ovarian tumor cells in combination with other active components that perform different specific functions for enhancing cellular uptake and efficiency of the main drugs specifically in cancer cells, limiting adverse side effects, and preventing the development and/or suppression of the existing drug resistance. In the proposed study, we plan to apply nanotechnology approaches to the development and evaluation of such multicomponent multifunctional nanotherapeutics. The long-term objective of the proposed research is to verify the hypothesis and develop a mixture (cocktail) of novel multifunctional Nanotechnology-based Drug Delivery Systems (NDDS) that will significantly increase the efficacy of the chemotherapy of primary ovarian cancer and intraperitoneal metastases while minimizing side effects on healthy organs. A hydroxyl terminated PAMAM-OH and internally quaternized and surface-acetylated Poly(amido amine) dendrimer (QPAMAM-NHAc) will be used as a nanocarrier to deliver anticancer drugs and siRNA, respectively. In addition, each NDDS will contain a tumor-specific targeting moiety (peptide) and one active component (anticancer drug or siRNA or fluorescent dye). Paclitaxel and cisplatin/carboplatin will be evaluated as anticancer drugs - cell death inducers. siRNA targeted to MDR1 and CD44 mRNA will be investigated as suppressors of pump resistance. siRNA targeted to BCL2 mRNA will be studied as a suppressor of nonpump resistance. Luteinizing Hormone-Releasing Hormone (LHRH) peptide will be used as ovarian cancer-specific targeting moiety. Established human multidrug resistant ovarian cancer cell lines as well as cells isolated from primary tumor and malignant ascites from patients with advanced multidrug resistant ovarian carcinoma will be used to create ectopic subcutaneous and orthotopic intraperitoneal models in nude mice. Intravenous systemic and intraperitoneal local administrations of NDDS will be compared. The results of the proposed research will be used to design novel multifunctional nanotechnology approaches for the treatment of different cancers. PUBLIC HEALTH RELEVANCE: We are proposing a novel nanotechnology-based approach for the effective treatment of ovarian cancer by simultaneous suppression of cellular resistance by siRNA targeted to MDR1, CD44 and BCL2 mRNA and cell death induction by two anticancer drugs (paclitaxel and cisplatin) with different mechanisms of action. The objective of the proposed research is to develop a novel mixture ("cocktail") of multifunctional nanocarrier- based drug delivery systems that will significantly increase the efficacy of the chemotherapy of primary ovarian cancer and intraperitoneal metastases while minimizing side effects of treatment on healthy organs.